GARDASIL(R) (Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant), the cervical cancer vaccine from Merck & Co., Inc., prevented 90 percent of external genital lesions caused by human papillomavirus (HPV) types 6, 11, 16 and 18 in a pivotal Phase III study in men aged 16 to 26. These are the only data evaluating efficacy of any HPV vaccine in preventing disease in males, and were presented for the first time this week at the European Research Organization on Genital Infection and Neoplasia (EUROGIN) International Multidisciplinary Conference.
The initial planned analysis of this study, an analysis of male study participants aged 16 to 26 who had not been infected with at least one of the four HPV types before the start of the study through one month after receiving their third dose of the vaccine or placebo, has been completed. This analysis was predetermined in the study protocol to be conducted after at least 32 cases of external genital lesions were observed. The study is ongoing, and additional data will be submitted to global regulatory agencies once available.
Merck remains on track to submit a supplemental Biologics License Application for GARDASIL to the U.S. Food and Drug Administration by the end of 2008 for the use of GARDASIL in boys and men ages 9 to 26 for the prevention of external genital lesions caused by HPV types 6, 11, 16 and 18. Other regulatory submissions around the world will occur as planned.
GARDASIL is not currently approved for males in the United States. GARDASIL is indicated for use in girls and young women 9 through 26 years of age for the prevention of cervical, vulvar and vaginal cancers caused by HPV types 16 and 18; genital warts caused by HPV types 6 and 11; and precancerous or dysplastic lesions caused by HPV types 6, 11, 16 and 18.
GARDASIL Reduced External Genital Lesions in Males by 90 Percent
The placebo-controlled, Phase III study was designed to determine the efficacy of GARDASIL in males against HPV 6, 11, 16, and 18-related external genital lesions, a composite endpoint that included: 1) genital warts (condylomata), 2) penile/perineal/perianal intraepithelial neoplasia (or PIN; PIN 2/3 can be pre-cursors to cancer) and 3) penile/perineal/perianal cancer. Penile/perineal/perianal is defined as related to or affecting the penis (penile), the area between the anus and the scrotum (perineal), or the opening of the rectum to the outside of the body (perianal).
The study evaluated approximately 3,400 heterosexual males 16 through 23 years of age and approximately 600 men 16 to 26 years of age who have sex with men. Participants were randomized in a 1-to-1 ratio to receive either GARDASIL or placebo at day one, two months and six months, with 36 months of planned follow-up from day one. At the time of vaccination, participants had no evidence of genital lesions, no history of genital warts and five or fewer lifetime sexual partners.
In the study, GARDASIL was 90.4 percent effective at reducing external genital lesions (3 cases in the vaccine group vs. 31 cases in placebo group; 95 percent CI: 69.2, 98.1, p-value
No vaccine-related serious adverse events were reported in this study. A slightly higher proportion of study participants reported injection-site adverse events in the vaccine group compared to placebo (60.1 percent vs. 53.7 percent).
GARDASIL Also Achieved Statistical Significance on Both Secondary Endpoints
Two secondary endpoints also were evaluated in this pivotal study and results from these analyses were presented at EUROGIN. GARDASIL was 85.6 percent effective at reducing persistent infection (15 cases in the vaccine group vs. 101 cases in the placebo group; 95 percent CI: 75.1, 92.2, p-value
Additional Important Information about GARDASIL
GARDASIL is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of GARDASIL.
The health care provider should inform the patient, parent or guardian that vaccination does not substitute for routine cervical cancer screening. Women who receive GARDASIL should continue to undergo cervical cancer screening.
GARDASIL is not recommended for use in pregnant women.
Vaccination with GARDASIL may not result in protection in all vaccine recipients. GARDASIL is not intended to be used for treatment of active genital warts, cervical, vaginal and vulvar cancers, cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN) or vaginal intraepithelial neoplasia (VaIN).
GARDASIL has not been demonstrated to provide protection against disease from vaccine and non-vaccine HPV types to which a woman has previously been exposed through sexual activity. GARDASIL has not been shown to protect against diseases due to HPV types not contained in the vaccine.
Not all vulvar and vaginal cancers are caused by human papillomavirus (HPV), and GARDASIL protects only against those vulvar and vaginal cancers caused by HPV types 16 and 18.
The most common adverse reaction was headache. Common adverse reactions that were observed among recipients of GARDASIL at a frequency of at least 1.0 percent and greater than placebo were fever, nausea, dizziness; and injection-site pain, swelling, erythema, pruritus, and bruising.
In addition, syncope has been reported following vaccination with GARDASIL, sometimes resulting in falling with injury. Observation for 15 minutes after administration is recommended.
Dosage and Administration for GARDASIL
GARDASIL is a ready-to-use, three-dose, intramuscular vaccine. GARDASIL should be administered in three separate intramuscular injections in the deltoid region of the upper arm or in the higher anterolateral area of the thigh. The following dosage schedule is recommended: first dose at elected date, second dose two months after the first dose and the third dose six months after the first dose.
Human Papillomavirus: A Virus that Affects Both Men and Women
According to the Centers for Disease Control and Prevention, in the U.S. alone, an estimated 20 million men and women are currently infected with HPV, and another 6.2 million people become newly infected each year. For most, HPV goes away on its own. However, certain low-risk types of HPV can cause external genital lesions. More than one million cases of external genital lesions in men and women occur each year in the U.S. and more than 30 million occur each year worldwide. In addition for women, certain high-risk types of HPV, if unrecognized and untreated, can lead to cervical cancer.
HPV is a virus that can infect the genital region of men and women. There are an estimated 30 to 40 types of genital HPV. HPV transmission can happen with any kind of intimate genital contact with someone who has HPV; sexual intercourse is not needed. Most sexually active people will have HPV at some time in their lives.
Other Information about GARDASIL
In 1995, Merck entered into a license agreement and research collaboration with CSL Limited of Australia relating to technology used in GARDASIL. GARDASIL also is the subject of other third-party licensing agreements.
About Merck
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.
Forward-Looking Statement
This press release contains “forward-looking statements” as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management’s current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck’s business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck’s Form 10-K for the year ended Dec. 31, 2007, and in any risk factors or cautionary statements contained in the Company’s periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.
Full Prescribing Information and Patient Product Information for GARDASIL(R) are attached and are also available at www.gardasil.com.
GARDASIL(R) is a registered trademark of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use GARDASIL safely and effectively. See full prescribing information for GARDASIL.
GARDASIL
(Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant)
Suspension for intramuscular injection
Initial U.S. Approval: 2006
RECENT MAJOR CHANGES
Indications (1) 9/2008
INDICATIONS AND USAGE
GARDASIL is a vaccine indicated in girls and women 9 through 26 years of age for the prevention of the following diseases caused by Human Papillomavirus (HPV) types included in the vaccine:
— Cervical, vulvar, and vaginal cancer caused by HPV types 16 and 18
— Genital warts (condyloma acuminata) caused by HPV types 6 and 11
And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18:
— Cervical intraepithelial neoplasia (CIN) grade 2/3 and Cervical adenocarcinoma in situ (AIS)
— Cervical intraepithelial neoplasia (CIN) grade 1
— Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3
— Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3
DOSAGE AND ADMINISTRATION
0.5-mL suspension for intramuscular injection at the following schedule: 0, 2 months, 6 months. (2.1)
DOSAGE FORMS AND STRENGTHS
— 0.5-mL suspension for injection as a single-dose vial and prefilled syringe (3) (11)
CONTRAINDICATIONS
— Hypersensitivity, including severe allergic reactions to yeast (a vaccine component), or after a previous dose of GARDASIL. (11).
WARNINGS AND PRECAUTIONS
— Women who receive GARDASIL should continue to undergo cervical cancer screening. (17.1)
— GARDASIL has not been demonstrated to provide protection against disease from vaccine and non-vaccine HPV types to which a woman has previously been exposed through sexual activity. (14.2)
— GARDASIL is not intended to be used for treatment of active genital warts; cervical, vulvar, and vaginal cancers; CIN; VIN; or VaIN. (5.1)
— GARDASIL has not been demonstrated to protect against diseases due to HPV types not contained in the vaccine. (14.3)
— Not all vulvar and vaginal cancers are caused by HPV and GARDASIL protects only against those vulvar and vaginal cancers caused by HPV 16 and 18.
ADVERSE REACTIONS
The most common adverse reaction was headache. Common adverse reactions (frequency of at least 1.0% and greater than AAHS control or saline placebo) are fever, nausea, dizziness; and injection-site pain, swelling, erythema, pruritus, and bruising. (6.1)
Syncope has been reported following vaccination with GARDASIL, sometimes resulting in falling with injury; observation for 15 minutes after administration is recommended. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Merck & Co., Inc. at 1-877-888-4231 or VAERS at 1-800-822-7967 or www.vaers.hhs.gov.
DRUG INTERACTIONS
GARDASIL may be administered concomitantly with RECOMBIVAX HB. (7.1)
USE IN SPECIFIC POPULATIONS
Safety and effectiveness of GARDASIL have not been established in the following populations:
— Pregnant women. Physicians are encouraged to register pregnant women exposed to GARDASIL by calling 1-800-986-8999 so that Merck can monitor maternal and fetal outcomes (8.1).
— Children below the age of 9 years and pediatric males of any age. (8.4)
— Women 27 years of age and older. (14.4).
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 09/2008
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Dosage
2.2 Method of Administration
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Limitations of GARDASIL Use and Effectiveness
5.2 Immunocompromised Individuals
5.3 Managing Allergic Reactions
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Post-Marketing Experience
7 DRUG INTERACTIONS
7.1 Use with RECOMBIVAX HB
7.2 Use with Hormonal Contraceptives
7.3 Use with Systemic Immunosuppressive Medications
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Prophylactic Efficacy – HPV Types 6, 11, 16, and 18 in Women 16 Through 26 Years of Age
14.2 Effectiveness of GARDASIL in Prevention of HPV Types 6-, 11-, 16-, or 18-Related Disease in Women 16 Through 26 Years of Age, Regardless of Current or Prior Exposure to Vaccine HPV Types
14.3 Effectiveness of GARDASIL in Prevention of Any HPV Type Related Genital Disease in Women 16 Through 26 Years of Age, Regardless of Current or Prior Infection with Vaccine or Non-Vaccine HPV Types
14.4 Other Studies
14.5 Immunogenicity
14.6 Studies with RECOMBIVAX HB
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Information for the Patient, Parent, or Guardian
17.2 FDA-Approved Patient Labeling
*Sections or subsections omitted from the full prescribing information are not listed.
GARDASIL(R)
(Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant) 9682308
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
GARDASIL(R)1 is a vaccine indicated in girls and women 9 through 26 years of age for the prevention of the following diseases caused by Human Papillomavirus (HPV) types included in the vaccine:
— Cervical, vulvar, and vaginal cancer caused by HPV types 16 and 18
— Genital warts (condyloma acuminata) caused by HPV types 6 and 11
And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18:
— Cervical intraepithelial neoplasia (CIN) grade 2/3 and Cervical adenocarcinoma in situ (AIS)
— Cervical intraepithelial neoplasia (CIN) grade 1
— Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3
— Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3
2 DOSAGE AND ADMINISTRATION
2.1 Dosage
GARDASIL should be administered intramuscularly as a 0.5-mL dose at the following schedule: 0, 2 months, 6 months. (See Clinical Studies (14.5).)
2.2 Method of Administration
Shake well before use. Thorough agitation immediately before administration is necessary to maintain suspension of the vaccine. GARDASIL should not be diluted or mixed with other vaccines. After thorough agitation, GARDASIL is a white, cloudy liquid. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the product if particulates are present or if it appears discolored.
GARDASIL should be administered intramuscularly in the deltoid region of the upper arm or in the higher anterolateral area of the thigh.
Do not administer GARDASIL intravenously, intradermally, or subcutaneously.
Syncope has been reported following vaccination with GARDASIL and may result in falling with injury; observation for 15 minutes after administration is recommended.
Single-Dose Vial Use
Withdraw the 0.5-mL dose of vaccine from the single-dose vial using a sterile needle and syringe and use promptly.
Prefilled Syringe Use With and Without Needle Guard (Safety) Device
Prefilled Syringe With Needle Guard (Safety) Device
Instructions for using the prefilled single-dose syringes preassembled with needle guard (safety) device
(OBJECT OMITTED)
NOTE: Please use the enclosed needle for administration. If a different needle is chosen, it should fit securely on the syringe and be no longer than 1 inch to ensure proper functioning of the needle guard device. Two detachable labels are provided which can be removed after the needle is guarded.
At any of the following steps, avoid contact with the Trigger Fingers to keep from activating the safety device prematurely.
Remove Syringe Tip Cap and Needle Cap. Attach Luer Needle by pressing both Anti-Rotation Tabs to secure syringe and by twisting the Luer Needle in a clockwise direction until secured to the syringe. Remove Needle Sheath. Administer injection per standard protocol as stated above under DOSAGE AND ADMINISTRATION. Depress the Plunger while grasping the Finger Flange until the entire dose has been given. The Needle Guard Device will NOT activate to cover and protect the needle unless the ENTIRE dose has been given. While the Plunger is still depressed, remove needle from the vaccine recipient. Slowly release the Plunger and allow syringe to move up until the entire needle is guarded. For documentation of vaccination, remove detachable labels by pulling slowly on them. Dispose in approved sharps container.
Prefilled Syringe Without Needle Guard (Safety) Device
This package does not contain a needle guard (safety device) or a needle. Shake well before use. Attach the needle by twisting in a clockwise direction until the needle fits securely on the syringe. Administer the entire dose as per standard protocol.
3 DOSAGE FORMS AND STRENGTHS
GARDASIL is a suspension for intramuscular administration available in 0.5-mL single dose vials and prefilled syringes. See Description (11) for the complete listing of ingredients.
4 CONTRAINDICATIONS
Hypersensitivity, including severe allergic reactions to yeast (a vaccine component), or after a previous dose of GARDASIL. (See Description (11).)
5 WARNINGS AND PRECAUTIONS
5.1 Limitations of GARDASIL Use and Effectiveness
The health care provider should inform the patient, parent, or guardian that vaccination does not substitute for routine cervical cancer screening. Women who receive GARDASIL should continue to undergo cervical cancer screening per standard of care.
GARDASIL has not been demonstrated to provide protection against disease from vaccine and non-vaccine HPV types to which a woman has previously been exposed through sexual activity. (See Clinical Studies (14.2).)
GARDASIL is not intended to be used for treatment of active genital warts; cervical, vulvar, and vaginal cancers; CIN; VIN; or VaIN.
GARDASIL has not been demonstrated to protect against diseases due to HPV types not contained in the vaccine. (See Clinical Studies (14.3).)
Not all vulvar and vaginal cancers are caused by HPV and GARDASIL protects only against those vulvar and vaginal cancers caused by HPV 16 and 18.
GARDASIL does not protect against genital diseases not caused by HPV.
Vaccination with GARDASIL may not result in protection in all vaccine recipients.
5.2 Immunocompromised Individuals
The immunologic response to GARDASIL may be diminished in immunocompromised individuals (See Drug Interactions (7.3)).
5.3 Managing Allergic Reactions
Appropriate medical treatment and supervision must be readily available in case of anaphylactic reactions following the administration of GARDASIL.
6 ADVERSE REACTIONS
Overall Summary of Adverse Reactions
Headache, fever, nausea, and dizziness; and local injection site reactions (pain, swelling, erythema, pruritus, and bruising) occurred after administration with GARDASIL.
Syncope has been reported following vaccination with GARDASIL and may result in falling with injury; observation for 15 minutes after administration is recommended.
Anaphylaxis has been reported following vaccination with GARDASIL.
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.
Studies in Girls and Women 9 Through 26 Years of Age
In 5 clinical trials (3 Amorphous Aluminum Hydroxyphosphate Sulfate (AAHS)-controlled, 1 saline placebo-controlled, and 1 uncontrolled), 8878 subjects were administered GARDASIL or AAHS control or saline placebo on the day of enrollment, and approximately 2 and 6 months thereafter, and safety was evaluated using vaccination report cards (VRC)-aided surveillance for 14 days after each injection of GARDASIL or AAHS control or saline placebo in these subjects. The subjects who were monitored using VRC-aided surveillance included 5088 girls and women 9 through 26 years of age at enrollment who received GARDASIL and 3790 girls and women who received AAHS control or saline placebo. Few subjects (0.1%) discontinued due to adverse reactions. The race distribution of the study subjects was as follows: 62.3% White; 17.6% Hispanic (Black and White); 6.8% Asian; 6.7% Other; 6.4% Black; and 0.3% American Indian.
Common Injection Site Adverse Reactions in Girls and Women 9 Through 26 Years of Age
The injection site adverse reactions that were observed among recipients of GARDASIL at a frequency of at least 1.0% and also at a greater frequency than that observed among AAHS control or saline placebo recipients are shown in Table 1.
Table 1 Injection-Site Adverse Reactions* ---------------------------------------------------------------------- GARDASIL AAHS Saline Adverse Reaction (N = Control Placebo (1 to 5 Days Postvaccination) 5088) ** (N = % (N = 320) 3470) % % ---------------------------------------------------------------------- Injection Site Pain 83.9 75.4 48.6 Swelling 25.4 15.8 7.3 Erythema 24.7 18.4 12.1 Pruritus 3.2 2.8 0.6 Bruising 2.8 3.2 1.6 ---------------------------------------------------------------------- * The injection-site adverse reactions that were observed among recipients of GARDASIL were at a frequency of at least 1.0% and also at a greater frequency than that observed among AAHS control or saline placebo recipients. **AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate
Evaluation of Injection-Site Adverse Reactions by Dose in Girls and Women 9 Through 26 Years of Age
An analysis of injection-site adverse reactions in girls and women by dose is shown in Table 2. Overall, 94.3% of girls and women who received GARDASIL judged their injection-site adverse reaction to be mild or moderate in intensity.
Table 2 Postdose Evaluation of Injection-Site Adverse Reactions (1 to 5 Days Postvaccination) ---------------------------------------------------------------------- GARDASIL AAHS Control* Saline Placebo (% occurrence) (% occurrence) (% occurrence) ====================================================================== Post- Post- Post- Post- Post- Post- Post- Post- Post- Adverse dose dose dose dose dose dose dose dose dose Reaction 1 2 3 1 2 3 1 2 3 N** = N = N = N = N = N = N = N = N = 5011 4924 4818 3410 3351 3295 315 301 300 ---------------------------------------------------------------------- Pain 63.4 60.7 62.7 57.0 47.8 49.6 33.7 20.3 27.3 Mild/Moderate 62.5 59.7 61.2 56.6 47.3 48.9 33.3 20.3 27.0 Severe 0.9 1.0 1.5 0.4 0.5 0.6 0.3 0.0 0.3 ---------------------------------------------------------------------- Swelling*** 10.2 12.8 15.1 8.2 7.5 7.6 4.4 3.0 3.3 Mild/Moderate 9.6 11.9 14.2 8.1 7.2 7.3 4.4 3.0 3.3 Severe 0.6 0.8 0.9 0.2 0.2 0.2 0.0 0.0 0.0 ---------------------------------------------------------------------- Erythema*** 9.2 12.1 14.7 9.8 8.4 8.9 7.3 5.3 5.7 Mild/Moderate 9.0 11.7 14.3 9.5 8.4 8.8 7.3 5.3 5.7 Severe 0.2 0.3 0.4 0.3 0.1 0.1 0.0 0.0 0.0 ---------------------------------------------------------------------- *AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate **N = Number of subjects with follow up ***Intensity of swelling and erythema was measured by size (inches): Mild = 0 to (1 to (2.
Common Systemic Adverse Reactions in Girls and Women 9 Through 26 Years of Age
Headache was the most commonly reported systemic adverse reaction in both treatment groups (GARDASIL = 28.2% and AAHS control or saline placebo = 28.4%). Fever was the next most commonly reported systemic adverse reaction in both treatment groups (GARDASIL = 13.0% and AAHS control or saline placebo = 11.2%).
Adverse reactions that were observed among recipients of GARDASIL, at a frequency of greater than or equal to 1.0% where the incidence in the GARDASIL group was greater than or equal to the incidence in the AAHS control or saline placebo group, are shown in Table 3.
Table 3 Common Systemic Adverse Reactions (GARDASIL => Control)* ---------------------------------------------------------------------- Adverse Reactions GARDASIL AAHS (1 to 15 Days Postvaccination) (N = control** 5088) or Saline % Placebo (N = 3790) % ---------------------------------------------------------------------- Pyrexia 13.0 11.2 Nausea 6.7 6.5 Dizziness 4.0 3.7 Diarrhea 3.6 3.5 Vomiting 2.4 1.9 Cough 2.0 1.5 Toothache 1.5 1.4 Upper respiratory tract infection 1.5 1.5 Malaise 1.4 1.2 Arthralgia 1.2 0.9 Insomnia 1.2 0.9 Nasal congestion 1.1 0.9 ---------------------------------------------------------------------- * The adverse reactions in this table are those that were observed among recipients of GARDASIL at a frequency of at least 1.0% and greater than or equal to those observed among AAHS control or saline placebo recipients. **AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate
Evaluation of Fever by Dose in Girls and Women 9 Through 26 Years of Age
An analysis of fever in girls and women by dose is shown in Table 4.
Table 4 Postdose Evaluation of Fever (1 to 5 Days Postvaccination) ---------------------------------------------------------------------- GARDASIL AAHS Control* or Saline (% occurrence) Placebo (% occurrence) ====================================================================== Temperature Postdose Postdose Postdose Postdose Postdose Postdose ( 1 2 3 1 2 3 (degree)F) N** = N = 4804 N = 4671 N = 3681 N = 3564 N = 3467 4945 ---------------------------------------------------------------------- (>=)100 to =)102 0.3 0.5 0.5 0.2 0.4 0.5 ---------------------------------------------------------------------- *AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate **N = Number of subjects with follow up
Serious Adverse Reactions in the Entire Study Population
A total of 237 subjects out of 25,274 total subjects (9- through 45-year-old girls and women; and 9- through 15-year-old boys) who received both GARDASIL (N = 13,686) and AAHS control (N = 11,004) or saline placebo (N = 584) reported a serious systemic adverse reaction following any vaccination visit during the clinical trials for GARDASIL.
Out of the entire study population (25,274 subjects), only 0.05% of the reported serious systemic adverse reactions were judged to be vaccine related by the study investigator. The most frequently reported serious systemic adverse reactions for GARDASIL compared to AAHS control or saline placebo and regardless of causality were:
Headache (0.02% GARDASIL (3 cases) vs. 0.02% AAHS Control (2 cases)),
Gastroenteritis (0.02% GARDASIL (3 cases) vs. 0.02% AAHS Control (2 cases)),
Appendicitis (0.03% GARDASIL (4 cases) vs. 0.01% AAHS Control (1 case)),
Pelvic inflammatory disease (0.02% GARDASIL (3 cases) vs. 0.04% AAHS Control (4 cases)),
Urinary tract infection (0.02% GARDASIL (2 cases) vs. 0.02% AAHS Control (2 cases)),
Pneumonia (0.02% GARDASIL (2 cases) vs. 0.02% AAHS Control (2 cases)),
Pyelonephritis (0.02% GARDASIL (2 cases) vs. 0.03% AAHS Control (3 cases)),
Pulmonary embolism (0.02% GARDASIL (2 cases) vs. 0.02% AAHS Control (2 cases)).
One case (0.007% GARDASIL: 0.0% AAHS Control or Saline Placebo) of bronchospasm; and 2 cases (0.02% GARDASIL: 0.0% AAHS Control or Saline Placebo) of asthma were reported as serious systemic adverse reactions that occurred following any vaccination visit.
In addition, there was 1 subject in the clinical trials, in the group that received GARDASIL, who reported two injection-site serious adverse reactions (injection-site pain and injection-site joint movement impairment).
Deaths in the Entire Study Population
Across the clinical studies, 24 deaths were reported in 25,274 (GARDASIL N = 13,686; AAHS Control N = 11,004, saline placebo N = 584) subjects (9- through 45-year-old girls and women; and 9- through 15-year-old boys). The events reported were consistent with events expected in healthy adolescent and adult populations. The most common cause of death was motor vehicle accident (4 subjects who received GARDASIL and 3 AAHS Control subjects), followed by overdose/suicide (2 subjects who received GARDASIL and 2 subjects who received AAHS Control), and pulmonary embolus/deep vein thrombosis (1 subject who received GARDASIL and 1 AAHS Control subject). In addition, there were 2 cases of sepsis, 1 case of pancreatic cancer, 1 case of arrhythmia, 1 case of pulmonary tuberculosis, 1 case of hyperthyroidism, 1 case of post-operative pulmonary embolism and acute renal failure, and 1 case of systemic lupus erythematosus in the group that received GARDASIL; 1 case of asphyxia, and 1 case of acute lymphocytic leukemia in the AAHS Control; and 1 case of medulloblastoma in the saline placebo group.
Systemic Autoimmune Disorders in Girls and Women 9 Through 26 Years of Age
In the clinical studies, 9- through 26-year-old girls and women were evaluated for new medical conditions that occurred over the course of follow-up. New medical conditions potentially indicative of a systemic autoimmune disorder seen in the group that received GARDASIL or AAHS control or saline placebo are shown in Table 5. This population includes all subjects who received at least one dose of GARDASIL or AAHS control or saline placebo, and had safety data available.
Table 5 Summary of Girls and Women 9 Through 26 Years of Age Who Reported an Incident Condition Potentially Indicative of Systemic Autoimmune Disorder After Enrollment in Clinical Trials of GARDASIL Regardless of Causality ---------------------------------------------------------------------- GARDASIL AAHS (N = Control* 10,706) or Saline Conditions Placebo (N = 9412) =================== n (%) n (%) ====================================================================== Arthralgia/Arthritis/Arthropathy** 120 (1.1) 98 (1.0) Autoimmune Thyroiditis 4 (0.0) 1 (0.0) Coeliac Disease 10 (0.1) 6 (0.1) Diabetes Mellitus Insulin-dependent 2 (0.0) 2 (0.0) Erythema Nodosum 2 (0.0) 4 (0.0) Hyperthyroidism*** 27 (0.3) 21 (0.2) Hypothyroidism+ 35 (0.3) 38 (0.4) Inflammatory Bowel Disease++ 7 (0.1) 10 (0.1) Multiple Sclerosis 2 (0.0) 4 (0.0) Nephritis2 (0.0) 5 (0.1) Optic Neuritis 2 (0.0) 0 (0.0) Pigmentation Disorderss. 4 (0.0) 3 (0.0) Psoriasis# 13 (0.1) 15 (0.2) Raynaud's Phenomenon 3 (0.0) 4 (0.0) Rheumatoid Arthritis++ 6 (0.1) 2 (0.0) Scleroderma/Morphea 2 (0.0) 1 (0.0) Stevens-Johnson Syndrome 1 (0.0) 0 (0.0) Systemic Lupus Erythematosus 1 (0.0) 3 (0.0) Uveitis 3 (0.0) 1 (0.0) ---------------------------------------------------------------------- All Conditions 245 (2.3) 218 (2.3) ---------------------------------------------------------------------- *AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate **Arthralgia/Arthritis/Arthropathy includes the following terms: Arthralgia, Arthritis, Arthritis reactive, and Arthropathy ***Hyperthyroidism includes the following terms: Basedow's disease, Goitre, Toxic nodular goitre, and Hyperthyroidism +Hypothyroidism includes the following terms: Hypothyroidism and thyroiditis ++Inflammatory bowel disease includes the following terms: Colitis ulcerative, Crohn's disease, and Inflammatory bowel disease
Nephritis includes the following terms: Nephritis, Glomerulonephritis minimal lesion, Glomerulonephritis proliferative ss.Pigmentation disorder includes the following terms: Pigmentation disorder, Skin depigmentation, and Vitiligo #Psoriasis includes the following terms: Psoriasis, Pustular psoriasis, and Psoriatic arthropathy ++Rheumatoid arthritis includes juvenile rheumatoid arthritis. One subject counted in the rheumatoid arthritis group reported rheumatoid arthritis as an adverse experience at Day 130. N = Number of subjects enrolled n = Number of subjects with specific new Medical Conditions NOTE: Although a subject may have had two or more new Medical Conditions, the subject is counted only once within a category. The same subject may appear in different categories.
Safety in Concomitant Use with RECOMBIVAX HB in Girls and Women 9 Through 26 Years of Age
The safety of GARDASIL when administered concomitantly with RECOMBIVAX HB hepatitis B vaccine (recombinant) was evaluated in an AAHS-controlled study of 1871 subjects with a mean age of 20.4 years. The race distribution of the study subjects was as follows: 61.6% White; 23.8% Other; 11.9% Black; 1.6% Hispanic (Black and White); 0.8% Asian; and 0.3% American Indian. The rates of systemic and injection-site adverse reactions were similar among subjects who received concomitant vaccination as compared with those who received GARDASIL or RECOMBIVAX HB hepatitis B vaccine.
6.2 Post-Marketing Experience
The following adverse events have been spontaneously reported during post-approval use of GARDASIL. Because these events were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or to establish a causal relationship to vaccine exposure.
Blood and lymphatic system disorders: Autoimmune hemolytic anemia, lymphadenopathy.
Gastrointestinal disorders: Nausea, pancreatitis, vomiting.
General disorders and administration site conditions: Asthenia, death, fatigue, malaise.
Immune system disorders: Autoimmune diseases, hypersensitivity reactions including anaphylactic/anaphylactoid reactions, bronchospasm, and urticaria.
Musculoskeletal and connective tissue disorders: Arthralgia, myalgia.
Nervous system disorders: Dizziness, Guillain-Barre syndrome, headache, motor neuron disease, paralysis, seizures, syncope sometimes resulting in falling with injury, transverse myelitis.
Vascular Disorders: Deep venous thrombosis, pulmonary embolus.
7 DRUG INTERACTIONS
7.1 Use with RECOMBIVAX HB
Results from clinical studies indicate that GARDASIL may be administered concomitantly (at a separate injection site) with RECOMBIVAX HB hepatitis B vaccine (recombinant) (See Clinical Studies (14.6)). Co-administration of GARDASIL with other vaccines has not been studied.
7.2 Use with Hormonal Contraceptives
In clinical studies, 13,293 subjects (GARDASIL N = 6644; AAHS control or saline placebo N = 6649) who had post-Month 7 follow-up used hormonal contraceptives for a total of 17,597 person-years (65.1% of the total follow-up time in the studies). Use of hormonal contraceptives or lack of use of hormonal contraceptives among study participants did not alter immune response in the per protocol efficacy (PPE) population.
7.3 Use with Systemic Immunosuppressive Medications
Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune responses to vaccines (See Warnings and Precautions (5.1)).
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B:
Reproduction studies have been performed in female rats at doses up to 300 times the human dose (on a mg/kg basis) and have revealed no evidence of impaired female fertility or harm to the fetus due to GARDASIL. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human responses, GARDASIL should be used during pregnancy only if clearly needed.
An evaluation of the effect of GARDASIL on embryo-fetal, pre- and postweaning development was conducted using rats. One group of rats was administered GARDASIL twice prior to gestation, during the period of organogenesis (gestation Day 6) and on lactation Day 7. A second group of pregnant rats was administered GARDASIL during the period of organogenesis (gestation Day 6) and on lactation Day 7 only. GARDASIL was administered at 0.5 mL/rat/occasion (approximately 300-fold excess relative to the projected human dose on a mg/kg basis) by intramuscular injection. No adverse effects on mating, fertility, pregnancy, parturition, lactation, embryo-fetal or pre- and postweaning development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis noted in this study. In addition, there were no treatment-related effects on developmental signs, behavior, reproductive performance, or fertility of the offspring. The effect of GARDASIL on male fertility has not been studied.
In clinical studies, women underwent urine pregnancy testing prior to administration of each dose of GARDASIL. Women who were found to be pregnant before completion of a 3-dose regimen of GARDASIL were instructed to defer completion of their vaccination regimen until resolution of the pregnancy.
GARDASIL is not indicated for women 27 years of age or older. However, safety data in women 16 through 45 years of age was collected, and 3620 women (GARDASIL N = 1796 vs. AAHS control or saline placebo N = 1824) reported at least 1 pregnancy each.
The overall proportions of pregnancies that resulted in an adverse outcome, defined as the combined numbers of spontaneous abortion, late fetal death, and congenital anomaly cases out of the total number of pregnancy outcomes for which an outcome was known (and excluding elective terminations), were 23.3% (423/1812) in subjects who received GARDASIL and 24.1% (438/1820) in subjects who received AAHS control or saline placebo.
Overall, 54 and 63 subjects in the group that received GARDASIL or AAHS control or saline placebo, respectively (3.0% and 3.5% of all subjects who reported a pregnancy in the respective vaccination groups), experienced a serious adverse reaction during pregnancy. The most common events reported were conditions that can result in Caesarean section (e.g., failure of labor, malpresentation, cephalopelvic disproportion), premature onset of labor (e.g., threatened abortions, premature rupture of membranes), and pregnancy-related medical problems (e.g., pre-eclampsia, hyperemesis). The proportions of pregnant subjects who experienced such events were comparable between the groups receiving GARDASIL and AAHS control or saline placebo.
There were 40 cases of congenital anomaly in pregnancies that occurred in subjects who received GARDASIL and 30 cases of congenital anomaly in pregnancies that occurred in subjects who received AAHS control or saline placebo.
Further sub-analyses were conducted to evaluate pregnancies with estimated onset within 30 days or more than 30 days from administration of a dose of GARDASIL or AAHS control or saline placebo. For pregnancies with estimated onset within 30 days of vaccination, 5 cases of congenital anomaly were observed in the group that received GARDASIL compared to 1 case of congenital anomaly in the group that received AAHS control or saline placebo. The congenital anomalies seen in pregnancies with estimated onset within 30 days of vaccination included pyloric stenosis, congenital megacolon, congenital hydronephrosis, hip dysplasia, and club foot. Conversely, in pregnancies with onset more than 30 days following vaccination, 35 cases of congenital anomaly were observed in the group that received GARDASIL compared with 29 cases of congenital anomaly in the group that received AAHS control or saline placebo.
Pregnancy Registry for GARDASIL
Merck & Co., Inc. maintains a Pregnancy Registry to monitor fetal outcomes of pregnant women exposed to GARDASIL. Patients and health care providers are encouraged to report any exposure to GARDASIL during pregnancy by calling (800) 986-8999.
8.3 Nursing Mothers
Women 16 Through 26 Years of Age
It is not known whether GARDASIL is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GARDASIL is administered to a nursing woman.
A total of 995 nursing mothers (vaccine N = 500, AAHS control N = 495) were given GARDASIL or AAHS control during the vaccination period of the clinical trials.
Overall, 21 and 10 infants of subjects who received GARDASIL or AAHS control, respectively (representing 4.2% and 2.0% of the total number of subjects who were breast-feeding during the period in which they received GARDASIL or AAHS control, respectively), experienced a serious adverse reaction.
In a post-hoc analysis of clinical studies, a higher number of breast-feeding infants (n = 6) whose mothers received GARDASIL had acute respiratory illnesses within 30 days post-vaccination of the mother as compared to infants (n = 2) whose mothers received AAHS control. In these studies, the rates of other adverse reactions in the mother and the nursing infant were comparable between vaccination groups.
8.4 Pediatric Use
Safety and effectiveness have not been established in pediatric patients below 9 years of age nor in pediatric males of any age.
Clinical studies of pediatric males 9 through 15 years of age were conducted and contributed safety data to the serious adverse reactions and deaths. (See Adverse Reactions (6.1).)
8.5 Geriatric Use
The safety and effectiveness of GARDASIL have not been evaluated in subjects aged 65 years and over.
10 OVERDOSAGE
There have been reports of administration of higher than recommended doses of GARDASIL.
In general, the adverse event profile reported with overdose was comparable to recommended single doses of GARDASIL.
11 DESCRIPTION
GARDASIL, Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant, is a non-infectious recombinant quadrivalent vaccine prepared from the purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV Types 6, 11, 16, and 18. The L1 proteins are produced by separate fermentations in recombinant Saccharomyces cerevisiae and self-assembled into VLPs. The fermentation process involves growth of S. cerevisiae on chemically-defined fermentation media which include vitamins, amino acids, mineral salts, and carbohydrates. The VLPs are released from the yeast cells by cell disruption and purified by a series of chemical and physical methods. The purified VLPs are adsorbed on preformed aluminum-containing adjuvant (Amorphous Aluminum Hydroxyphosphate Sulfate). The quadrivalent HPV VLP vaccine is a sterile liquid suspension that is prepared by combining the adsorbed VLPs of each HPV type and additional amounts of the aluminum-containing adjuvant and the final purification buffer.
GARDASIL is a sterile suspension for intramuscular administration. Each 0.5-mL dose contains approximately 20 mcg of HPV 6 L1 protein, 40 mcg of HPV 11 L1 protein, 40 mcg of HPV 16 L1 protein, and 20 mcg of HPV 18 L1 protein.
Each 0.5-mL dose of the vaccine contains approximately 225 mcg of aluminum (as Amorphous Aluminum Hydroxyphosphate Sulfate adjuvant), 9.56 mg of sodium chloride, 0.78 mg of L-histidine, 50 mcg of polysorbate 80, 35 mcg of sodium borate,
After thorough agitation, GARDASIL is a white, cloudy liquid.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
HPV only infects human beings. Animal studies with analogous animal papillomaviruses suggest that the efficacy of L1 VLP vaccines may involve the development of humoral immune responses. Human beings develop a humoral immune response to the vaccine, although the exact mechanism of protection is unknown.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
GARDASIL has not been evaluated for the potential to cause carcinogenicity or genotoxicity.
GARDASIL administered to female rats at a dose of 120 mcg total protein, which corresponds to approximately 300-fold excess relative to the projected human dose, had no effects on mating performance, fertility, or embryonic/fetal survival.
14 CLINICAL STUDIES
CIN 2/3 and AIS are the immediate and necessary precursors of squamous cell carcinoma and adenocarcinoma of the cervix, respectively. Their detection and removal has been shown to prevent cancer; thus, they serve as surrogate markers for prevention of cervical cancer. In the clinical studies, cases of CIN 2/3 and AIS were the efficacy endpoints to assess prevention of cervical cancer. In addition, cases of vulvar and vaginal intraepithelial neoplasia (VIN 2/3 and VaIN 2/3) were the efficacy endpoints to assess prevention of HPV-related vulvar and vaginal cancers, and observations of external genital lesions were the efficacy endpoints for the prevention of genital warts.
Efficacy was assessed in 4 AAHS-controlled, double-blind, randomized Phase II and III clinical studies. The first Phase II study evaluated the HPV 16 component of GARDASIL (Protocol 005 or Study 1, N = 2391) and the second evaluated all components of GARDASIL (Protocol 007 or Study 2, N = 551). The Phase III studies evaluated GARDASIL in 5442 (Study 3 or Protocol 013 (FUTURE I)) and 12,157 (Study 4 or Protocol 015 (FUTURE II)) subjects. Together, these four studies evaluated 20,541 women 16 through 26 years of age at enrollment with a mean age of 20.0 years. The race distribution of the study subjects was as follows: 70.4% White; 12.2% Hispanic (Black and White); 8.8% Other; 4.6% Black; 3.8% Asian; and 0.2% American Indian. The median duration of follow-up was 4.0, 3.0, 3.0, and 3.0 years for Study 1, Study 2, Study 3, and Study 4, respectively. Subjects received vaccine or AAHS control on the day of enrollment and 2 and 6 months thereafter. Efficacy was analyzed for each study individually and for all studies combined according to a prospective clinical plan.
Overall, 73% of subjects were naive (i.e., PCR (Polymerase Chain Reaction) negative and seronegative for all 4 vaccine HPV types) to all 4 vaccine HPV types at enrollment.
A total of 27% of subjects had evidence of prior exposure to or ongoing infection with at least 1 of the 4 vaccine HPV types. Among these subjects, 74% had evidence of prior exposure to or ongoing infection with only 1 of the 4 vaccine HPV types and were naive (PCR negative and seronegative) to the remaining 3 types.
In subjects who were naive (PCR negative and seronegative) to all 4 vaccine HPV types, CIN, genital warts, VIN, and VaIN caused by any of the 4 vaccine HPV types were counted as endpoints.
Among subjects who were positive (PCR positive and/or seropositive) for a vaccine HPV type at Day 1, endpoints related to that type were not included in the analyses of prophylactic efficacy. Endpoints related to the remaining types for which the subject was naive (PCR negative and seronegative) were counted.
For example, in subjects who were HPV 18 positive (PCR positive and/or seropositive) at Day 1, lesions caused by HPV 18 were not counted in the prophylactic efficacy evaluations. Lesions caused by HPV 6, 11, and 16 were included in the prophylactic efficacy evaluations. The same approach was used for the other types.
14.1 Prophylactic Efficacy – HPV Types 6, 11, 16, and 18 in Women 16 Through 26 Years of Age
GARDASIL was administered without prescreening for presence of HPV infection and the efficacy trials allowed enrollment of subjects regardless of baseline HPV status (i.e., PCR status or serostatus). Subjects with current or prior HPV infection with an HPV type contained in the vaccine were not eligible for prophylactic efficacy evaluations for that type.
The primary analyses of efficacy with respect to HPV types 6, 11, 16, and 18 were conducted in the per-protocol efficacy (PPE) population, consisting of individuals who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naive (PCR negative in cervicovaginal specimens and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month Postdose 3 (Month 7). Efficacy was measured starting after the Month 7 visit.
GARDASIL was efficacious in reducing the incidence of CIN (any grade including CIN 2/3); AIS; genital warts; VIN (any grade); and VaIN (any grade) related to vaccine HPV types 6, 11, 16, or 18 in those who were PCR negative and seronegative at baseline (Table 6).
In addition, individuals who were already infected with 1 or more vaccine-related HPV types prior to vaccination were protected from precancerous cervical lesions and external genital lesions caused by the other vaccine HPV types.
Table 6 Analysis of Efficacy of GARDASIL in the PPE* Population** of 16- Through 26-Year-Old Women for Vaccine HPV Types ---------------------------------------------------------------------- GARDASIL AAHS Control Population -------------------- % Efficacy (95% CI) Number Number N of N of cases cases ====================================================================== HPV 16- or 18-related CIN 2/3 or AIS ---------------------------------------------------------------------- Study 1*** 755 0 750 12 100.0 (65.1, 100.0) ---------------------------------------------------------------------- Study 2 231 0 230 1 100.0 (-3744.9, 100.0) ---------------------------------------------------------------------- Study 3 2201 0 2222 36 100.0 (89.2, 100.0) ---------------------------------------------------------------------- Study 4 5306 2 5262 63 96.9 (88.2, 99.6) ---------------------------------------------------------------------- Combined Protocols++ 8493 2 8464 112 98.2 (93.5, 99.8) ====================================================================== HPV 16-related CIN 2/3 or AIS ---------------------------------------------------------------------- Combined Protocols++ 7402 2 7205 93 97.9 (92.3, 99.8) ====================================================================== HPV 18-related CIN 2/3 or AIS ---------------------------------------------------------------------- Combined Protocols++ 7382 0 7316 29 100.0 (86.6, 100.0) ====================================================================== HPV 16- or 18-related VIN 2/3 ---------------------------------------------------------------------- Study 2 231 0 230 0 Not calculated ---------------------------------------------------------------------- Study 3 2219 0 2239 6 100.0 (14.4, 100.0) ---------------------------------------------------------------------- Study 4 5322 0 5275 4 100.0 (-50.3, 100.0) ---------------------------------------------------------------------- Combined Protocols++ 7772 0 7744 10 100.0 (55.5, 100.0) ====================================================================== HPV 16- or 18-related VaIN 2/3 ---------------------------------------------------------------------- Study 2 231 0 230 0 Not calculated ---------------------------------------------------------------------- Study 3 2219 0 2239 5 100.0 (-10.1, 100.0) ---------------------------------------------------------------------- Study 4 5322 0 5275 4 100.0 (-50.3, 100.0) ---------------------------------------------------------------------- Combined Protocols++ 7772 0 7744 9 100.0 (49.5, 100.0) ---------------------------------------------------------------------- HPV 6-, 11-, 16-, or 18-related CIN (CIN 1, CIN 2/3) or AIS ---------------------------------------------------------------------- Study 2 235 0 233 3 100.0 (-138.4, 100.0) ---------------------------------------------------------------------- Study 3 2241 0 2258 77 100.0 (95.1, 100.0) ---------------------------------------------------------------------- Study 4 5388 9 5374 145 93.8 (88.0, 97.2) ---------------------------------------------------------------------- Combined Protocols++ 7864 9 7865 225 96.0 (92.3, 98.2) ====================================================================== HPV 6-, 11-, 16-, or 18-related Genital Warts ---------------------------------------------------------------------- Study 2 235 0 233 3 100.0 (-139.5, 100.0) ---------------------------------------------------------------------- Study 3 2261 0 2279 58 100.0 (93.5, 100.0) ---------------------------------------------------------------------- Study 4 5404 2 5390 132 98.5 (94.5, 99.8) ---------------------------------------------------------------------- Combined Protocols++ 7900 2 7902 193 99.0 (96.2, 99.9) ====================================================================== HPV 6- and 11-related Genital Warts ---------------------------------------------------------------------- Combined Protocols++ 6932 2 6856 189 99.0 (96.2, 99.9) ---------------------------------------------------------------------- * The PPE population consisted of individuals who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naive (PCR negative and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month postdose 3 (month 7). **See Table 7 for analysis of vaccine impact in the general population ***Evaluated only the HPV 16 L1 VLP vaccine component of GARDASIL ++Analyses of the combined trials were prospectively planned and included the use of similar study entry criteria N = Number of subjects with at least 1 follow-up visit after Month 7 CI = Confidence Interval Note 1: Point estimates and confidence intervals are adjusted for person-time of follow-up Note 2: The first analysis in the table (i.e., HPV 16- or 18-related CIN 2/3, AIS or worse) was the primary endpoint of the vaccine development plan. Note 3: Study 1 = Protocol 005; Study 2 = Protocol 007; Study 3 = Protocol 013; and Study 4 = Protocol 015 Note 4: Table 6 does not include cases due to non-vaccine HPV types AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate
Prophylactic efficacy against overall cervical and genital disease related to HPV 6, 11, 16, and 18 in an extension phase of Study 2, that included data through month 60, was noted to be 100% (95% CI: 12.3%, 100.0%) among subjects in the per protocol population naive to the relevant HPV types.
GARDASIL was efficacious against HPV disease caused by HPV types 6, 11, 16, and 18 in women who were naive for those specific HPV types at baseline.
14.2 Effectiveness of GARDASIL in Prevention of HPV Types 6-, 11-, 16-, or 18-Related Disease in Women 16 Through 26 Years of Age, Regardless of Current or Prior Exposure to Vaccine HPV Types
The clinical trials included women regardless of current or prior exposure to vaccine HPV types, and additional analyses were conducted to evaluate the impact of GARDASIL with respect to HPV 6-, 11-, 16-, and 18-related cervical and genital disease in these women. Here, analyses included events arising among women regardless of baseline PCR status and serostatus, including HPV infections that were present at the start of vaccination as well as events that arose from infections that were acquired after the start of vaccination.
The impact of GARDASIL in women regardless of current or prior exposure to a vaccine HPV type is shown in Table 7. Impact was measured starting 1 month Postdose 1. Prophylactic efficacy denotes the vaccine’s efficacy in women who are naive (PCR negative and seronegative) to the relevant HPV types at vaccination onset. Vaccine impact in women who were positive for vaccine HPV infection, as well as vaccine impact among women regardless of baseline vaccine HPV PCR status and serostatus are also presented. The majority of CIN and genital warts, VIN, and VaIN related to a vaccine HPV type detected in the group that received GARDASIL occurred as a consequence of HPV infection with the relevant HPV type that was already present at Day 1.
There was no clear evidence of protection from disease caused by HPV types for which women were PCR positive regardless of serostatus at baseline.
Table 7 Effectiveness of GARDASIL against HPV 6, 11, 16, or 18 Related Disease in Women 16 Through 26 Years of Age, Regardless of Current or Prior Exposure to Vaccine HPV Types ---------------------------------------------------------------------- GARDASIL or HPV AAHS 16 L1 Control % Reduction Endpoints Analysis VLP (95% CI) Vaccine ------------------ N Cases N Cases ====================================================================== Prophylactic Efficacy* 9346 4 9407 155 97.4 (93.3, 99.3) ----------------------------------------------- HPV 16- or 18-related HPV 16 CIN 2/3 or AIS and/or HPV 148** 18 Positive at Day 1 2870 142 2898 -- ----------------------------------------------- Women regardless of Current 51.8 (41.1, or Prior 60.7)+ Exposure to HPV 16 or 18 ** 9836 146 9904 303 ====================================================================== Prophylactic Efficacy* 8642 1 8673 34 97.0 (82.4, 99.9) ----------------------------------------------- HPV 16- or 18-related HPV 16 VIN 2/3 or VaIN 2/3 and/or HPV 18 Positive at Day 1 1880 8 1876 4 -- ----------------------------------------------- Women regardless of Current 76.3 (50.0, or Prior 89.9)+ Exposure to HPV 16 or 18*** 8955 9 8968 38 ====================================================================== Prophylactic Efficacy* 8630 16 8680 309 94.8 (91.5, 97.1) ----------------------------------------------- HPV 6-, 11-, 16-, 18- HPV 6, HPV related CIN (CIN 1, 11, HPV 16, CIN 2/3) or AIS and/or HPV 186++ 213++ 18 Positive at Day 1 2466 2437 -- ----------------------------------------------- Women regardless of Current 61.5 (54.6, or Prior 67.4)+ Exposure to Vaccine HPV Types*** 8819 202 8854 522 ====================================================================== Prophylactic Efficacy* 8761 10 8792 252 96.0 (92.6, 98.1) ----------------------------------------------- HPV 6-, 11-, 16-, or HPV 6, HPV 18-related Genital 11, HPV 16, Warts and/or HPV 18 Positive at Day 1 2501 51# 2475 55# -- ----------------------------------------------- Women regardless of Current 80.3 (73.9, or Prior 85.3)+ Exposure to Vaccine HPV Types*** 8955 61 8968 307 ---------------------------------------------------------------------- Prophylactic Efficacy* 7769 9 7792 246 96.4 (9
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